DESCRIPTION (adapted from the application) Diabetes remains one of the leading causes of lower limb amputation and is a contributing factor in up to 70 percent of the greater than 55,000 amputations annually. In the majority of diabetic subjects, the underlying factor which contributes to eventual amputation is the diabetic foot ulcer. The overall goal of this application is to determine the capacity of topical retinoid treatment to induce changes in the skin of diabetic patients that would reduce the incidence of ulcer formation and improve healing of wounds when they did occur. We know from recent studies that topical retinoid treatment improves histological structure and biochemical function of skin damaged by age and/or excessive exposure to solar radiation. Since diabetic skin demonstrates the same atrophic changes seen in aged human skin, it might be possible to improve structure and function in diabetic skin with the same approach. If one can improve the structure and function of diabetic skin in a similar fashion, such skin would be (in theory) more resistant to ulcer formation, and would heal better if wounding did occur. A three-part approach is proposed to achieve the overall goal of this application. We will in Specific Aim I assess fibroblast growth, connective tissue synthesis, matrix metalloproteinase (MMP) elaboration, vascular development and reactivity and indices of oxidative stress in hip skin from diabetic patients, including those with microangiopathic complications, and evaluate the effects of topical retinol treatment on these parameters. In Specific Aim 2, the goal will be to assess fibroblast growth, connective tissue synthesis, MMP elaboration, vascular development and reactivity and indices of oxidative stress in diabetic skin predisposed to the development of ulceration utilizing organ culture techniques. The effects of retinol treatment on these parameters will be assessed. Specific Aim 3 will make use of a rodent model of diabetes. Here we will determine the effects of topical retinol treatment on dermal structure/function in streptozotocin diabetic (STZ-D) rats and compare abrasion wound formation and healing in control rats, STZ-D rats and STZ-D rats that have been pretreated with topical retinol.